In an investigation of the factors that regulate hepatocyte proliferation, we are employing several animal models which include rats subjected to partial hepatectomy or to liver necrosis from various toxic chemical agents, and mice infected with lethal doses of A59 murine hepatitis virus. In some models, insulin and glucagon exert a substantial growth promoting influence when there is a liver deficiency, but the hormones are unable by themselves to initiate growth in animals whose livers are intact. Epidermal growth factor (EGF), on the other hand, is capable of stimulating hepatocyte proliferation in vivo in normal animals with intact livers, especially in combination with insulin and glucagon. We are studying the interactions of these and other hormones in relation to both protection of liver cells from injury and promotion of hepatic regeneration, and seeking the mechanisms through which they operate, both in vivo and in vitro.